7-{8 2-(2-Thioxo-4-thiazolin-3-yl)-acetamido{9 {0 cephalosporanic acid derivatives

ABSTRACT

The invention presents gram-positive and gram-negative antibacterial agents of the structural formula   IN WHICH R1 and R2 are independently -H or alkyl of 1 to 6 carbon atoms, and when taken together, R1 and R2 are trimethylene; R3 is -H, alkyl of 1 to 6 carbon atoms or methylthioethyl; N IS 0 OR 1, WITH THE PROVISO THAT WHEN N IS 1, R3 is -H; and A is a 7-amino-cephalosporin or 6-amino-penicillin moiety.

United States Patent [191 Teller et al.

[4 1 Dec. 16, 1975 1 7 2-( 2-THIOXO-4-THIAZOLIN-3-YL)- ACETAMIDO] CEPHALOSPORANIC ACID DERIVATIVES [75] Inventors: Daniel M. Teller, Devon; John H.

Sellstedt, Pottstown; Charles J. Guinosso, King of Prussia, all of Pa.

[73] Assignee: American Home Products Corporation, New York, NY.

[22] Filed: Oct. 2, 1974 [21] Appl. No.: 511,155

[52] US. Cl 260/243 C; 260/306.7; 424/246 [51] Int. Cl. C07D 501/34; C07D 501/46 [58] Field of Search 260/243 C [56] References Cited UNITED STATES PATENTS 3,627,760 12/1971 Bickel et al. 260/243 C FOREIGN PATENTS OR APPLICATIONS 1,816,824 7/1969 Germany Primary Examiner-Donald G. Daus Assistant ExaminerDiana G. Rivers Attorney, Agent, or FirmRichard K. Jackson [5 7] ABSTRACT The invention presents gram-positive and gramnegative antibacterial agents of the structural formula 13 Claims, No Drawings 7-[2-(2-TI-IIOXO-4-TI'IIAZOLIN 3-YL)- ACETAMIDO] CEPHALOSPORANIC ACID DERIVATIVES 1 i DESCRIPTION or. THE INVENTION In accordance with this invention there is provided antibacterial agents of the formula;

4 CHZR in which R is H, (lower)alkanoyloxy,

N at and R is H, an alkali metal or the ammonium ion. The term (lower)alkanoyloxy means the lower fatty acid acyloxy radicals such as acetoxy, propionyloxy, butyroyloxy, valeroyloxy, and the like. The 6-amino-penicillin moiety referred to above as A presents the structural formula:

s CH

I a 0 N C02R5 in which R in which R has the definition stated above.

The compounds of this invention are prepared by coupling an acid of the formula:

in which R, R R and n are defined above, with a 7-amino-cephalosporin or 6-amino-penicillin derivative via the conventional methods and employing con- 'ventional condensing agents such as isobutyl chloroformate, dicyclohexyl carbodiimide or carbonyl diimidazole, as disclosed by Micetich, et al., J. Med. Chem. 15, 333 (1972); Spencer et al., J. Med. Chem. 9, 746 (1966) and US. Pat. No. 3,338,896.

The acids referred to in the preceding paragraph are prepared by the method of Mathes et al., J .A.C.S. 72, 1879 (1950) via the reaction wherein R, R R and n are' defined above.

The compounds of this invention are antibacterial agents effective against gram-positive and gram-negative test organisms as well as penicillin resistant staphylococcus at an inhibitory concentration at or below 250 micrograms per milliliter using the well-known and scientifically accepted agar serial dilution technique. Thus, the compounds of this invention are useful in controlling bacterial infections amenable to treatment with penicillins and cephalosporins by inhibiting their growth. 1 i

The following examples are presented for the puspose of illustrating the invention and are not to be construed as limitations on the true scope of the contribution. The biological activity data presented at the conclusion of each example illustrate the compounds activity against specific bacteria of the designated strain in terms of the minimum inhibitory concentration of the compound in micrograms per milliliter to completely inhibit the test organism. The abbreviations for the bacterium are:

ST AU Staphylococcus aureus BA SU Bacillus sublilis NE CA Neisseria catarrhalis HE SP Herellea species ES CO Escherichia coli PR VU Proteus vulgaris v SA PA Salmonella paratyphi BO BR Bordetella brochiseptica EN AE Enterobacter aerogenes ES lN Escherichia intermedia KL PN Klebsiella pneumoniae In the working examples, the expression ACA refers to aminocephalosporanic acid, ADCA refers to aminodesacetoxy-cephalosporanic acid, and APA refers to aminopenicillanic acid.

EXAMPLE 1 7-[2-(4-Methyl-2-thioxo-4-thiazolin-3-yl)acetamido]- cephalosporanic acid.

tetrahydrofuran is evaporated in vacuo at a temperature below 40C. A mixture of water (300 ml) and ethyl acetate (80 ml) is added to the residue, the mixture shaken thoroughly and the organic layer discarded. Ethyl acetate (400 ml) is added to the aqueous layer, the mixture cooled to 5 C and acidified to pH 2.0 with hydrochloric acid. A precipitate forms, which is filtered off, slurried in water, acidified to pH 2.0 with 10% hydrochloric acid (300 ml) containing ethyl acetate (100 ml) and filtered togive the title compound, 1.80 g; m.p. 177-180C (d); )t f 5.60, 5.77, 5.87, 6.00 ,u; NMR has 2.00 and 2.19 ppm singlets.

Elemental Analysis for C H N O S Calcd: C, 43.33; H, 3.86; N, 9.47; S, 21.69. Found: C, 42.83; H, 3.84; N, 9.26; S, 20.94.

The sodium salt of the above compound is prepared by slurryingthe compound (3.45 g, 0.0078 moles) in water ml) at 5C and adding dropwise over 15 minutes 1M sodium hydroxide 7.78 ml, 0.0078 moles) giving a final pH 5.4. The mixture is filtered and freezedriedto give the sodium salt of the title compound, 2.55 g yellow solid; mp. 180-220C. (d); A 5.68, 5.99 1.1.; NMR has 2.07 and 2.18 ppm singlets.

Elemental Analysis for c,,,H,,N o,s,Na.1H o; Calcd: C, 39.75; H, 3.78; N, 8.69; S, 19.89;H O, 3.73. Found: C, 39.35; H, 3.71; N, 8.35; S, 19.76;H O, 5.00.

BA SU 6633 .0152 ST AU 6539P .244 ST AU Smith .244 ST AU CHP .976 ST AU 53-180 .488 NE CA 8193 31.3 ES CO 9637 15.6 SA PA 11737 3.90 KL PN 10031 3.90 BO BR 4617 250 PR VU 6896 31.3

The compound of example I possess in vivo activity against Escherichia coli 920 and Proteus vulgaris PR347 at a curative dose (CD of 5.65 milligrams and 6.67 milligrams per mouse, respectively, as determined by the subcutaneous administration of the compound of example lat 0 time and 6 hours after intraperitoneal infection with the infective agent.

EXAMPLE 2 3-Methyl-7-[2-(4-methyl-2thioxo-4-thiazolin-3- yl)acetamido]8-oxo-5-thia-l-azabicyclo[4.2.0]oct- 2-ene-2-carboxylic acid.

Using the method described in Example 1 but substituting 7-ADCA (2.14 g, 0.01 moles) for 7-ACA gives the title compound, 0.74 g; mp. 232234C.(d); A 5.62, 5.79, 5.96 t; NMR has 2.05 and 2.22 ppm singlets.

Elemental Analysis for C H N O S: Calcd: C, 43.64; H, 3.92; N, 10.91; S, 24.96. Found: C, 43.84; H, 4.07; N, 10.83; S, 24.24.

The sodium salt of the above compound is prepared by slurrying the compound (5.0 g, 0.013 moles) in water ml) at 5C and adding dropwise over 15 minutes 1M sodium hydroxide (13.0 ml, 0.013 moles) giving a final pH 6.2. The mixture is filtered and freezedried to give the sodium salt of the title compound, 4.70 g colorless solid; mp. 245255C.(d); h 5.60, 5.81, 6.19 a; NMR has 1.95 and 2.17 ppm singlets.

Elemental Analysis for C H N O S NalH O: Calcd: C, 39.55; H, 3.79; N, 9.89; S, 22.62; H O, 4.24. Found: C, 38.89; H, 3.62; N, 9.58; S, 20.76; H O, 6.52.

BA SU 6633 .976 ST AU 6538P 3.90 ST AU Smith 3.90 ST AU CHP 15.6 ST AU 53-180 7.81 SA PA 11737 KL PN 10031 125 EXAMPLE 3 6-[2-( 4-Methy1-2-thioxo-4-thiazolin-3-yl)acetamido]- penicillanic acid.

Using the method described in Example 1 but substituting 6-APA (2.16 g, 0.01 moles) for 7-ACA does not give a precipitate on acidifying to pH 2.0 with hydrochloric acid. Therefore, the organic layer is separated, the aqueous layer extracted with ethyl acetate (120 ml) the organic layer and extract combined, washed with brine, dried over anydrous sodium sulfate and evaporated in vacuo at a temperature below 40C. The residue is dissolved in methylene chloride (50 ml) and added dropwise to pentane (500 ml) with vigorous stirring to give the title compound, 2.80 g.; mp. 162166C.(d); 5.57, 5.72, 5.90 1.; NMR has 1.52 and 1.17 ppm singlets.

Elemental Analysis for C H N O S Calcd: C,

' 43.41; H, 4.42; N, 10.85; S, 24.84. Found: C, 42.22; H,

BA SU 6633 .122 ST AU 6538? .122 ST AU Smith .122 ST AU CHP 7.81 ST AU 53-180 31.3 NE CA 8193 1.95 ES CO 9637 125 SA PA 1 1737 15.6

PR VU 6896 125 HE SP 9955 62.5

EXAMPLE 4 7-[3-(4-Methyl-2-thioxo-4-thiazo1in3-y1)propionamido]cephalosporanic acid.

BA sU 6633 .244 ST AU 6538p .244 ST AU Smith .244 ST AU CHP 1.95 ST AU 53-180 1.95 NE CA 8193 62.5 ES co 9637 62.5 SA PA 11737 15.6 KL PN 10031 313 PR vu 6896 62.5

EXAMPLE 5 3-Methy1-7-[ 3-( 4-methyl-2-thioxo-4-thiazolin-3- yl)propionamido]-8-oxo-5-thia-1-azabicyclo[4.2.- 0]oct-2-ene-2-carboxylic acid.

Using the method described in Example 3 but substituting 7-ADCA (2.14 g, 0.01 mole) for 6-APA and 3-(4-methyl-2-thioxo-4-thiazolin-3-y1)propionic acid (2.03 g, 0.01 moles) for 2-(4-methyl-2-thioxo-4-thiazo- 5 lin-3-yl)acetic acid and triturating the residue with diethyl ether (50ml) gives the title compound, 2.59 g; mp. 195-l98C. (d); A 5.62, 5.99 ,u.; NMR has 2.02 and 2.31 ppm singlets.

1O fOI C 5H 7N3O4S3: Calc d: C,

45.12; H, 4.29; N, 10.52; S, 24.10. Found: C, 45.73; H, 4.53; N, 10.09; S, 21.71.

BA sU 6633 3.90 ST AU 6538P .976 ST AU Smith .488 ST AU CHP 7.81 ST AU 53-180 7.81 NE CA 8193 125 sA PA 11737 250 KL PN 10031 62.5 PR vU 6896 250 EXAMPLE 6 6-[ 3- 4-Methy1-2-thioxo-4-thiazolin-3 -yl )propionamido]penicil1anic acid.

Using the method described in Example 3 but substituting 4-methyl-2-thioxo-4-thiazoline-3-propionic acid (2.03 g, 0.01 mole) for 4-methy1-2-thioxo-4-thiazoline- 3-acetic acid gives the title compound, 3.23 g; mp.

8791C; A 5.62, 5.70, 6.02 [.L; NMR has 1.48,

1.60, 2.30 ppm singlets.

Elemental Analysis for C H N O S Cald: C, 44.89; H, 4.77; N, 10.47; S, 24.00. Found: C, 43.46; H, 5.20; N, 9.88; S, 26.49.

BA SU 6633 .488 ST AU 65381 .122 8'1 AU Smith .122

ST AU CHP 7.81 ST AU 53-180 62.5 NE CA 8193 1.95 ES CO 9637 125 SAPA 11737 31.3 PR vU 6896 250 HE SP 9955 125 55 EXAMPLE 7 7- 2-( 3 ,4,5 ,6-Tetrahydro-2-thioxo-2H-cyclopentathiazol-3-yl)aeetamido]cephalosporanic acid.

Using the method described in Example 5 but substituting 7-ACA (2.72, 0.01 moles) for 7-ADCA and 3,4,5,6-tetrahydro-2-thioxo-2H-cyclopentathiazole-3- acetic acid (2.15 g, 0.01 moles) for 4-methyl-2-thioxo- 4-thiazoline-3-propionic acid gives the title compound, 0.95 g; mp 152155C.; A 5.59, 5.68, 5.82, 5.97 NMR has 2.00 ppm singlet.

Elemental Analysis for C H N O S Calcd: C, 46.04; H, 4.08; N, 8.95; S, 20.49. Found: C, 46.06; H, 4.34; N, 8.74; S, 20.67.

BA so 6633 .061 ST AU 6538P .244 ST AU Smith .244 ST AU c111 .976 ST AU 53-180 .488 NE CA 8193 15.6 ES C 9637 62.5 SA PA 11737 62.5 x1. PN 10031 7.81 PR V0 6896 31.3

EXAMPLE 8 3-Methyl-8-oxo-7-[ 2-( 3 ,4, 5 ,6-tetrahydro-2-thioxo-2H- cyclopentathiazol-3-yl )acetamido ]-5-thia- 1 -azabicyclo[4.2.0loct-2-ene-2-carb0xylic acid.

Using the method described in Example 1 but substituting 7-ADCA (2.14 g, 0.01 moles) for 7-ACA and 3,4,5,6-tetrahydro-2-thioxo-2H-cyclopentathiazole-3- acetic acid (2.15 g, 0.01 moles) for 4-methyl-2-thioxo- 4-thiazoline-3-acetic acid gives the title compound, 1.70 g; mp. 192196C.; A 5.51, 5.60 (shoulders), 5.80, 5.89 ;1.; NMR has 2.00 p. singlet.

Elemental Analysis for C H N O S Calcd: C, 46.04; H, 4.08; N, 8.95; S, 20.49. Found: C, 46.06; H, 4.34; N, 8.74; S, 20.67.

BA su 6633 .976 ST AU 6538P 1.95 ST AU Smith .976 ST AU CHP 7.81 sr AU 53-120 3.90 NE CA 8193 250 KL PN 10031 125 EXAMPLE 9 6-[ 2-( 3 ,4, 5 ,6-Tetrahydro-2-thioxo-2H-cyclop entathiazol-3-yl)acetamido]penicillanic acid.

Using the method described in Example 3 but substituting 3,4,5,6-tetrahydro-2-thioxo-2-H-cyclopentathiazol-3-acetic acid (2.15 g, 0.01 moles) for 4-methyl- 2-thioxo-4-thiazoline-3-acetic acid gives the title compound, 3.22 g; mp. l20124C.; )t 5.58, 5.70, 5.88 p; NMR has 1.54 and 1.67 ppm singlets.

Elemental Analysis for C H N O S Calcd: C, 46.49; H, 4.63; N, 10.17; S, 23.28. Found: C, 46.30; H, 4.77; N, 9.88; S, 22.18.

BA su 6633 .976

ST AU 6538P .122

ST AU Smith .122

ST AU CHP 3.90

ST AU 53-180 62.5

NE CA 8193 1.95

ES c0 9637 250 SA PA 11737 125 PR vu 6896 250 EXAMPLE 1O 7-[2-(4-Methyl-2-thioxo-4-thiazolin-3-yl)propionamido]cephalosporanic acid.

Using the method described in Example 5 but substituting 7-ACA (2.72 g, 0.01 moles) for 7-ADCA and a,4-dimethyl-2-thioxo-4-thiazo1ine-3-acetic acid (2.03

g, 0.01 moles) for 4-methyl-2-thioxo-4-thiazoline-3- propionic acid gives the title compound, 1.90 g; mp. 120C; A 5.03, 5.22, 5.84 (shoulder), 6.00 pa shoulder; NMR has 2.0] and 2.26 ppm singlets.

Elemental Analysis for C H N O S Calcd: C, 44.62; H, 4.18; N, 9.18; S, 21.02. Found: C, 45.12; H, 4.54; N, 8.90; S, 20.80.

BA SU 6633 1.95 ST AU 65381 7.81 ST AU Smith 7.81 ST AU CHP 31.3 ST AU 53-180 31.3 ES CO 9637 31.3 ES [N 651 SA PA 1 1737 15.6 EN AE 13048 250 KL PN 1003] 15.6 PR VU 6896 31.3

EXAMPLE l1 3-Methy1-7-[2-(4-methyl-2-thioxo-4-thiazolin-3- yl)propionamid0]-8-oxo-5-thia-1-azabicyc1o[4.2.- 0]oct-2-ene-2-carboxylic acid.

Using the method described in Example 5 but substituting 01,4-dimethy1-2-thioxo-4-thiazoline-3-acetic acid (2.03 g, 0.01 moles) for 4-methy1-2-thioxo-4-thiaz0- line-3-propionic acid gives the title compound, 1.75 g; mp. 108109C.; A,,,,, 5.65, 5.80 (shoulder), 5.90 .1.; NMR has 1.63, 1.74 and 2.17 ppm singlets.

Elemental Analysis for C l-I N O S Calcd: C, 45.12; H, 4.29; N, 10.52; S, 24.10. Found: C, 43.45; H, 4.83; N, 8.60; S, 19.64.

EA S0 6633 7.81 ST AU 65381 313 ST AU Smith 15.6 ST AU CHF 125 ST AU 53 1s0 125 KL PN 10031 250 EXAMPLE l2 6-[2-(4-Methyl-2-thioxo-4-thiazolin-3 -yl)propionamido1penicillanic acid.

BA SU 6633 .244 ST AU 65381 .488 ST AU Smith .488 ST AU CHP 31.3 ST AU 53-180 125 NE CA 8193 7.81 SA PA 1 1737 125 PR VU 6896 250 HE SP 9955 125 EXAMPLE 13 Using the method described in Example 5 but substituting 7-ACA (2.72 g, 0.01 moles) for 7-ADCA and 2-thioxo-4-thiazolidine-3-acetic acid (1.75g, 0.01 moles) for 4-methyl-2-thioxo-4-thiazoline-3-propionic acid gives the title compound, 1.47 g; mp. 142144C. (d); 5.60, 5.78, 5.97 .1.; NMR has 2.08 ppm singlet.

Elemental Analysis for C H N O S Calcd: C, 41.96; H, 3.52; N, 9.79; S, 22.41. Found: C, 42.05; H, 3.73; N, 9.46; S, 23.05. t

The sodium salt of the above compound is prepared by slurrying the compound (5.0 g, 0.0118 moles) in water (160 ml) at 5C and adding dropwise over 15 minutes 1M sodium hydroxide (11.7 ml, 0.0117 moles) giving a final pH 5.8. The mixture is filtered and freezedried to give the sodium salt of the title compound, 3.87 g colorless solid; mp. 205-230C. (d); A 5.63, 5.75 (shoulder), 5.96 11.; NMR has 2.07 ppm singlet.

Elemental Analysis for C H N O S Nal l/2H O: Calcd: C, 37.62; H, 3.58; N, 8.78; S, 20.11. Found: C, 37.58; H, 3.25; N, 8.66; S, 18.98.

3-Methyl-8-oxo7[2-(2-thioxo-4-thia2olin-3 yl)acetamido]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2- carboxylic acid.

Using the method described in Example 5 but substituting 2-thioxo-4-thiazolidine-3-acetic acid (1.75 g, 0.01 moles) for 4-methyl-2-thioxo-4-thiazoline-3-propionic acid gives the title compound, 1.07 g; mp. 92-96C. (d); A 5.62, 5.84, 6.00 p. (shoulder); NMR has 2.03 ppm singlet.

Elemental Analysis for C H N O4S Calcd: C, 42.05; H, 3.53; N, 11.32; S, 25.91. Found: C, 43.48; H, 4.16; N, 9.46; S, 22.16.

The sodium salt of the above compound is prepared by slurrying the compound (3.50 g, 0.00945 moles) in water (85 ml) at 5C and adding dropwise over 15 minutes 1M sodium hydroxide (9.45 ml, 0.00945 moles) giving a final pH 6.0. The mixture is filtered and freeze-dried to give the sodium salt of the title .compound, 3.25 g; mp. 210-225C. (d); A 3.00, 5.68 ;1.; NMR has 1.97 ppm singlet.

Elemental Analysis for C, H N O S Na.l H O: Calcd: C, 37.97; H, 3.44; N, 10.22; S, 23.40; H O, 4.38. Found: C, 38.38; H, 3.43; N, 10.15; S, 21.85; H O, 7.53.

BA su 6633 .976 ST AU 6538P 3.90 ST AU Smith 3.90 ST AU CHF 15.6 ST AU 53-180 7.81

ES co 9637 SA PA 11737 62.5 KL PN 10031 62.5 PR vu 6896 250 EXAMPLE 15 6-[2-(2-Thioxo-4-thiazolin-3-yl)acetamido]penicillanic acid.

BA so 6633 .976 ST AU 6538P .488 ST AU Smith .488 ST AU CHP 15.6 ST AU 53480 62.5 NE CA 8193 7.81 ES co 9637 250 SA PA 11737 7.81 PR vu 6896 125 EXAMPLE 16 7-[4-(Methylthio)-2-(4-methyl-2-thioxo-4-thiazolin-3- yl)butyramido]cephalosporanic acid.

BA SU 6633 7.81 ST AU 6538P 15.6 ST AU Smith 7.81 ST AU CHP 62.5 ST AU 53-480 31.3 ES CO 9637 625 ES IN 65- 125 SA PA 11737 62.5 EN AE 13048 250 KL PN 10031 62.5

EXAMPLE 17 3-Methyl-7-[4-(methylthio)-2-(4-methyl-2-thioxo-4- thiazolin-3-yl )butyramido ]-8-oxo-5-thial -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.

Using the method described in Example 3 but substituting 7-ADCA (2.14 g, 0.01 moles) for 6-APA and BA su 6633 7.8l ST AU 6538P 31.3 ST AU Smith 31.3 ST AU CHF 250 51" AU 53-180 250 EXAMPLE 18 6-[4-(Methylthio)-2-(4-methyl-2-thioxo-4-thiazolin-3- yl)butyramido]penicillanic acid.

Using the method described in Example 3 but substituting 4-methyl-a-(2-methylthioethyl)-2-thioxo-4- thiazoline-3-acetic acid (2.63 g, 0.01 moles) for 4- methyl-2-thioxo-4-thiazoline-3-acetic acid gives the title compound, 3.08 g; mp. lO2-107C.; )t 5.57, 5.70 (shoulder); 5.88 11; NMR has 1.51, 1.57, 2.07 ppm singlets.

Elemental Analysis for C,-,H N O S Calcd: C,

44.23; H, 5.02; N, 9.10; S, 27.78. Found: C, 44.40; H, 3

BA 50 6633 1.95 ST AU 6538? 1.95 ST AU Smith 1.95 ST AU CHP 31.3 ST AU 53-180 31.3 NE CA 8193 7.81 SA PA 11737 125 HE SP 9955 250 What is claimed is: l. A compound of the formula:

(CH -CHCNH- l S 5 CO R in which R and R are independently H or alkyl of l to 6 carbon atoms, and when taken together, R and R are trimethylene;

R is H, alkyl of l to 6 carbon atoms or methylthioethyl;

R is -H, (lower)alkanoyloxy, or

R is H, an alkali metal or the ammonium ion; and

n is 0 or 1, with the proviso that when n is l, R is 2. The compound of claim 1 which is 7-[2-(4-methyl- 2-thioxo-4-thiazolin-3-yl)acetamido]cephalosporanic acid.

3. The compound of claim 1 which is 3-methyl-7-[2- (4-methyl-2-thioxo-4-thiazolin-3-yl)acetamido]-8-oxo- S-thial -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.

4. The compound of claim 1 which is 7-[3-(4-methyl- 2-thioxo-4-thiazolin-3-yl)propionamido]cephalosporanic acid.

5. The compound of claim 1 which is 3-methyl-7-[3- (4-methyl-2-thioxo-4-thiazolin-3-yl)propionamido]-8- 0 oxo-5-thial -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.

6. The compound of claim 1 which is 7-[2(3,4,5,6-

tetrahydro-2-thioxo-2H-cyclopentathiazol-3- yl)acetamido]cephalospianic acid.

7. The compound of claim 1 which is 3-methyl-8- oxo-7-[2-(3,4,5,6-tetrahydro-2-thioxo-2H-cyclopentathiazo1-3-yl )-acetamido ]-5-thial -azabicyclo 4. 2.- 0]oct-2-ene-2-carboxylic acid.

8. The compound of claim 1 which is 7-[2-(4-methyl- 2-thioxo-4-thiazolin-3-yl)propionamidolcephalosporanic acid.

9. The compound of claim 1 which is 3-methyl-7-[2- (4-methyl-2-thioxo-4-thiazolin-3-yl)propionamido]-8- oxo-5 -thial -azabicyclo 4.2.0]oct-2-ene-2-carboxylic acid.

10. The compound of claim 1 which is 7-[2-( 2-thioxo-4-thiazolin-3-yl)acetamido]cephalosporanic acid.

11. The compound of claim 1 which is 3-methyl-8- oxo-7-[2 (2 thioxo-4-thiazolin-3-yl)acetamido]-51thia- 1-azabicyclo-[4.2.0loct-2-ene-2-carboxylic acid.

12. The compound of claim 1 which is 7-[4-(methylthio)-2-(4-methyl-2-thioXo-4-thiazolin-3- yl)butyramido]cephalosporanic acid.

13. The compound of claim 1 which is 3-methyl-7-[4- (methylthio)-2-(4-methy1-2-thioxo-4-thiazolin-3- yl)butyramido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct- 2-ene-2-carboxy1ic acid. 

1. A COMPOUND OF THE FORMULA:
 2. The compound of claim 1 which is 7-(2-(4-methyl-2-thioxo-4-thiazolin-3-yl)acetamido)cephalosporanic acid.
 3. The compound of claim 1 which is 3-methyl-7-(2-(4-methyl-2-thioxo-4-thiazolin-3-yl)acetamido)-8-oxo-5-thia-1 -azabicyclo(4.2.0)oct-2-ene-2-carboxylic acid.
 4. The compound of claim 1 which is 7-(3-(4-methyl-2-thioxo-4-thiazolin-3-yl)propionamido)cephalosporanic acid.
 5. The compound of claim 1 which is 3-methyl-7-(3-(4-methyl-2-thioxo-4-thiazolin-3-yl)propionamido)-8-oxo-5-thia-1-azabicyclo(4.2.0)oct-2-ene-2-carboxylic acid.
 6. The compound of claim 1 which is 7-(2-(3,4,5,6-tetrahydro-2-thioxo-2H-cyclopentathiazol-3 -yl)acetamido)cephalospianic acid.
 7. The compound of claim 1 which is 3-methyl-8-oxo-7-(2-(3,4,5, 6-tetrahydro-2-thioxo-2H-cyclopentathiazol-3-yl)-acetamido)-5-thia-1 -azabicyclo(4.2.0)oct-2-ene-2-carboxylic acid.
 8. The compound of claim 1 which is 7-(2-(4-methyl-2-thioxo-4-thiazolin-3-yl)propionamido)cephalosporanic acid.
 9. The compound of claim 1 which is 3-methyl-7-(2-(4-methyl-2-thioxo-4-thiazolin-3-yl)propionamido)-8-oxo-5-thia-1-azabicyclo(4.2.0)oct-2-ene-2-carboxylic acid.
 10. The compound of claim 1 which is 7-(2-(2-thioxo-4-thiazolin-3-yl)acetamido)cephalosporanic acid.
 11. The compound of claim 1 which is 3-methyl-8-oxo-7-(2-(2-thioxo-4-thiazolin-3-yl)acetamido)-5-thia-1 -azabicyclo-(4.2.0)oct-2-ene-2-carboxylic acid.
 12. The compound of claim 1 which is 7-(4-(methylthio)-2-(4-methyl-2-thioxo-4-thiazolin-3 -yl)butyramido)cephalosporanic acid.
 13. The compound of claim 1 which is 3-methyl-7-(4-(methylthio)-2-(4-methyl-2-thioxo-4-thiazolin-3-yl)butyramido)-8-oxo-5-thia-1-azabicyclo(4.2.0)oct-2-ene-2-carboxylic acid. 